Updated enzyme kinetic model DNAMET will be finalized, including all the real numerical values of constants, and maximum velocities necessary to obtain stability and convergence. Subsequent two-dimensional and three-dimensional isobols will be obtained. Combination experiments will be conducted in mice to verify the interactions. The drug metabolism parameters, as functions of dosage, obtained, for 12 drugs, by the "deterministic" version of DRGFIT, will be utilized as input on SIVFIT, written in deterministic form also to optimize timing, sequence and dosage of drugs. Spectrofluorimetric studies of several dyes, interacting with DNA, RNA and histones, will be carried out under different ionic conditions to further optimize the differential staining of individual cell components. With our automated multi-parameter FMF analysis of living cells, we follow quantatively and simultaneously the kinetic response to chemical agents (using our newly introduced FPI technique) of each cell subpopulation of the bone marrow, melanoma B-16 and its metastates, intestinal mucosa of the small and large bowel. FACS-1 will be utilized to identify and further characterize each cell population, sorted by scatter and/or fluorescence. By monitoring real time the kinetic response to drug regiments, suggested by our previous experimentation and computer simulation, we are aiming at the best cell synchrony of the melanoma tumor cells compatible with a high differential response of normal tissues. Survival experiments will be carried out, using the most promising treatments, in C-57 black mice, bearing melanoma B-16 tumors, to attempt selective killing of metastatic cells after the amputation of the tumor-bearing leg.